Compounded solutions of diclofenac and lidocaine and methods

ABSTRACT

A compounded topical solution may include approximately 85% to approximately 95% (v/v) diclofenac sodium topical solution, 1.5% (w/w), and approximately 5% to approximately 15% (v/v) lidocaine hydrochloride topical solution, 4% USP.

FIELD OF THE INVENTION

The present application relates to compounded medications. Inparticular, the present application relates to compounded topicalsolutions and methods of making and using such compounded topicalsolutions.

BACKGROUND

Diclofenac sodium topical solution is a non-steroidal anti-inflammatorydrug (NSAID) indicated for the treatment of signs and symptoms ofosteoarthritis of the knee. For the relief of such signs and symptoms,the recommended dose of diclofenac sodium topical solution, 1.5% (w/w),is 40 drops on each painful knee, 4 times a day.

Lidocaine hydrochloride topical solution is a local anesthetic agentindicated for the production of topical anesthesia of accessible mucousmembranes of the oral and nasal cavities and proximal portions of thedigestive tract. When used as a spray, or when applied by cottonapplicators or packs, as when instilled into a cavity, the suggesteddosage of Lidocaine Hydrochloride Topical Solution, 4%, is 1 to 5 mL (40to 200 mg lidocaine HCl), i.e., 0.6 to 3 mg/kg or 0.3 to 1.5 mg/lb bodyweight. When spraying, the solution is to be transferred from itsoriginal container to an atomizer.

SUMMARY

In one aspect, a compounded topical solution may include approximately85% to approximately 95% (v/v) diclofenac sodium topical solution, 1.5%(w/w). The compounded topical solution may further include approximately5% to approximately 15% (v/v) lidocaine hydrochloride topical solution,4% USP.

In one example, the diclofenac sodium topical solution, 1.5% (w/w), ispresent in an amount between approximately 90% and approximately 93%(v/v) of the compounded topical solution and the lidocaine hydrochloridetopical solution, 4% USP, is present in an amount between approximately7% and approximately 10% (v/v) of the compounded topical solution.

In another example, the diclofenac sodium topical solution, 1.5% (w/w),is present in an amount approximately 90% (v/v) or more of thecompounded topical solution and the lidocaine hydrochloride topicalsolution, 4% USP, is present in an amount approximately 7% (v/v) or moreof the compounded topical solution.

In yet another example, the diclofenac sodium topical solution, 1.5%(w/w), is present in an amount approximately 91.7% (v/v) of thecompounded topical solution and the lidocaine hydrochloride topicalsolution, 4% USP, is present in an amount approximately 8.32% (v/v) ofthe compounded topical solution.

In still yet another example, the compounded topical solution includesapproximately 1.47% (w/v) diclofenac sodium and approximately 0.333%(w/v) lidocaine hydrochloride.

In another aspect, a method of making a compounded topical solutionincludes combining diclofenac sodium topical solution, 1.5% (w/w), andlidocaine hydrochloride topical solution, 4% USP. The method may furtherinclude mixing the combined diclofenac sodium topical solution, 1.5%(w/w), and lidocaine hydrochloride topical solution, 4% USP. Thediclofenac sodium topical solution, 1.5% (w/w), may be combined in anamount between approximately 85% and approximately 95% (v/v) of thecompounded topical solution and the lidocaine hydrochloride topicalsolution, 4% USP, may be combined in an amount between approximately 5%and approximately 15% (v/v) of the compounded topical solution.

In one example, the diclofenac sodium topical solution, 1.5% (w/w), iscombined in an amount between approximately 90% and approximately 93%(v/v) of compounded topical solution and the lidocaine hydrochloridetopical solution, 4% USP, is combined in an amount between approximately7% and approximately 10% (v/v) of the compounded topical solution.

In another example, the diclofenac sodium topical solution, 1.5% (w/w),is combined in an amount approximately 90% (v/v) or more of thecompounded topical solution and the lidocaine hydrochloride topicalsolution, 4% USP, is combined in an amount approximately 7% (v/v) ormore of the compounded topical solution.

In yet another example, the diclofenac sodium topical solution, 1.5%(w/w), is combined in an amount approximately 91.7% (v/v) of thecompounded topical solution and the lidocaine hydrochloride topicalsolution, 4% USP, is combined in an amount approximately 8.32% (v/v) ofthe compounded topical solution.

In still yet another example, the compounded topical solution includesapproximately 1.47% (w/v) diclofenac sodium and approximately 0.333%(w/v) lidocaine hydrochloride.

The above-described and other features and advantages of the presentdisclosure will be appreciated and understood by those skilled in theart from the following detailed description, drawings, and appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E are exemplary chromatograms of standard, untreated, heattreated, acid treated (45° C.), and acid treated (65° C.) DiclofenacSodium samples, respectively, generated in a degradation study accordingto various embodiments described herein; and

FIGS. 2A-2D are exemplary chromatograms of standard, untreated, heattreated, and acid treated Lidocaine HCl samples, respectively, generatedin a degradation study according to various embodiments describedherein.

DETAILED DESCRIPTION

The present embodiments may relate to topically delivered or deliverablesolutions of compounded medications for treatment of various ailments,such as inflammation or pain.

The compounded medications may typically include topical solutions thatmay be topically administered at a body surface. In one embodiment, acompounded topical solution for the effective administration of multiplemedications simultaneously for treatment of one or more ailments may beprovided. The compounded topical solution may include at least twoactive agents including a local anesthetic and a Non-SteroidalAnti-Inflammatory Drug (NSAID). The compounded topical solution mayinclude all or some of the active agents in aqueous solution. In someembodiments, the topical solution comprises a compounded topicalsolution comprising at least two commercially available topicalsolutions that are compounded together. For example, a compoundedtopical solution may include a commercially available NSAID topicalsolution and a commercially available local anesthetic topical solution.In some embodiments, the compounded topical solution may further includemultiple local anesthetics or NSAIDs obtained from commerciallyavailable solutions, commercially available creams, bulk powders, groundtablets, or combination thereof of such local anesthetics or NSAIDS.

In one embodiment, the compounded topical solution includes additionalactive agents selected from one or more anticonvulsants, nervedepressants, muscle relaxants, NMDA (N-Methyl-D-aspartate) receptorantagonists, opiate or opioid agonists, antidepressants, and/or otheractive agents.

The compounded topical solutions may be topically applied via anysuitable mode of administration of the solution for the ailment treated,including, e.g., spray, drops, atomizer, wash, swab, sponge, absorbentdressing, instillation or irrigation. Ailments treated may includeconditions such as inflammation, rheumatoid arthritis, osteoarthritis,lateral epicondylitis (tennis elbow), medial epicondylitis (golfer'selbow), chondromalacia patellae—CMP (runner's knee), tendonitis/carpeltunnel, soft tissue pain, fibromyalgia, diabetic neuropathy, peripheralneuropathy, neck pain, back pain, localized pain, plantar fasciitis,achilles tendonitis, tarsal tunnel—post-op massage, or heel pain. Thecompounded topical solution may exhibit excellent storagecharacteristics, and avoid separation and/or degradation of the activeingredients in the aqueous environment for substantial lengths of time.

As introduced above, the compounded topical solution may include a NSAIDtopical solution compounded with a local anesthetic topical solution.The NSAID component of the topical compounded solution may act to blockthe synthesis of prostaglandins by inhibiting cyclooxygenase-2 andcyclooxygenase-1, for example. In various embodiments, the NSAID may beselected from one or more salicylic acid derivatives (e.g., aspirin,diflunisal, salsalate, trilisate), one or more propionic acids (e.g.,flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin), one or moreacetic acids (e.g., diclofenac, etodolac, indomethacin, ketorolac,nabumetone, sulindac, tolmetin), one or more fenamates (e.g.,meclofenamate), one or more oxicams (meloxicam, piroxicam), or one ormore COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib), orcombinations thereof. For example, in one embodiment, the NSAID topicalsolution comprises a benzeneacetic acid derivative such as diclofenac orpharmaceutically acceptable salt thereof provided in an aqueoussolution. In various embodiments, the local anesthetic may be selectedfrom lidocaine, prilocaine, benzocaine, or combination thereof. Thelocal anesthetic may be provided in an aqueous solution and compoundedwith the NSAID topical solution. One or both of the NSAID topicalsolution or the local anesthetic topical solution may be commerciallyavailable topical solutions. For example, the NSAID topical solution mayinclude a commercially available diclofenac, or pharmaceuticallyacceptable salt thereof, topical solution and the local anesthetictopical solution may include a commercially available lidocaine, orpharmaceutically acceptable salt thereof, topical solution. Inembodiments including one or more additional NSAIDs, local anesthetics,or both, the additional actives may be provided in commerciallyavailable solutions, creams, or pure powders or crushed commercialtablets and then combined with the compounded topical solution or acomponent thereof.

In various embodiments, the compounded topical solution may include adiclofenac topical solution comprising diclofenac in an aqueoussolution. The diclofenac topical solution may be a commerciallyavailable diclofenac topical solution, such as diclofenac sodiumsolution for topical administration. The diclofenac sodium solution maycontain, for example, 1.5% (w/w), diclofenac sodium wherein each 1 mL ofsolution contains approximately 16.05 mg of diclofenac sodium. In oneembodiment, the diclofenac solution comprises a diclofenac sodiumsolution, 1.5% (w/w), such as that which is manufactured under the tradename PENNSAID® by Nuvo Manufacturing, Varennes, Quebec, Canada orDiclofenac Sodium Topical Solution, 1.5% (w/w), manufactured by ApotexInc. Toronto, Ontario, Canada M9L 1T9 for Apotex Corp. Weston, Fla.33326 for treating the pain of osteoarthritis of the knee. Thediclofenac solution may also contain various inactive ingredients suchas dimethyl sulfoxide USP (DMSO, 45.5% w/w), ethanol, glycerin,propylene glycol and purified water. In one embodiment, the diclofenacsolution comprises a diclofenac sodium solution marketed under the tradename PENNSAID® and manufactured by Nuvo Manufacturing, Varennes, Quebec,Canada, in a 2% (w/w) diclofenac solution for treating the pain ofosteoarthritis of the knee. Each gram of solution may containapproximately 20 mg of diclofenac sodium and various inactiveingredients such as dimethyl sulfoxide USP (DMSO, 45.5% w/w), ethanol,purified water, propylene glycol, and hydroxypropyl cellulose. In otherembodiments, other concentrations of diclofenac solution, such asdiclofenac sodium solutions, may be used.

In various embodiments, the compounded topical solution may include alidocaine topical solution comprising lidocaine in an aqueous solution.The lidocaine topical solution may be a commercially available lidocainetopical solution, such as lidocaine hydrochloride solution for topicaladministration. The lidocaine hydrochloride solution may contain, forexample, 4% lidocaine (w/v) wherein each mL includes 40 mg lidocaineHCl. For example, in one embodiment, the lidocaine topical solution maybe Lidocaine Hydrochloride Topical Solution USP, 4% manufactured by IGILabs, Inc., Buena, N.J., in 50 mL screw cap glass bottles. The lidocainehydrochloride topical solution may contain various inactive ingredientssuch as methylparaben, purified water, and sodium hydroxide to adjust pHto 6.0-7.0.

The compounded topical solution formulated by combining a lidocainehydrochloride topical solution and diclofenac sodium topical solutionmay include relatively low concentrations of the active ingredientscompared to conventional topical formulations including one or more ofthe active ingredients. Due to the formulation and combination describedherein, the present compounded topical solution may provide similareffectiveness while having an increased safety profile. The increasedsafety profile may be especially beneficial to patients with gastricbleeds, on blood thinners, etc. The compounded composition may alsoprovide local anesthetics benefits while promoting deeper penetrationinto the skin and leveraging DMSO in the diclofenac sodium solutionembedded into the compounded topical cream, e.g., 45.5% (w/w) of thediclofenac sodium solution compounded with the lidocaine hydrochloridesolution.

In various embodiments, the compounded topical solution comprisesdiclofenac or diclofenac sodium at a concentration between 0.1% and 1.9%and lidocaine or lidocaine hydrochloride at a concentration of between0.1% and 3.9%. In one example, the compounded topical solution includesapproximately 0.5% or more, approximately 1.0% or more, or approximately1.45% or more diclofenac or diclofenac sodium and approximately 0.2% ormore, approximately 0.28% or more, or approximately 0.3% or morelidocaine or lidocaine hydrochloride. As used herein, the termapproximately means+/−10% of the stated value it modifies. In someembodiments, the compounded topical solution includes betweenapproximately 1.0% and approximately 1.9%, approximately 1.1% andapproximately 1.8%, approximately 1.2% and approximately 1.7%,approximately 1.2% and approximately 1.6%, approximately 1.2% andapproximately 1.5%, approximately 1.2% and approximately 1.4%,approximately 1.2% and approximately 1.3%, approximately 1.3% andapproximately 1.6%, approximately 1.3% and approximately 1.5%,approximately 1.3% and approximately 1.4%, approximately 1.4% andapproximately 1.6%, approximately 1.4% and approximately 1.5% (w/v)diclofenac or diclofenac sodium and between approximately 1.0%,approximately 0.2% and approximately 0.8%, approximately 0.2% andapproximately 0.7%, approximately 0.2% and approximately 0.6%,approximately 0.2% and approximately 0.5%, approximately 0.2% andapproximately 0.4%, approximately 0.2% and approximately 0.3%,approximately 0.3% and approximately 0.7%, approximately 0.3% andapproximately 0.6%, approximately 0.3% and approximately 0.5%,approximately 0.3% and approximately 0.4%, approximately 0.330% andapproximately 0.340% (w/v) lidocaine or lidocaine hydrochloride. Forexample, in various embodiments, the compounded topical solutioncomprises between approximately 1.0% and approximately 2.0%, such asbetween approximately 1.3% and approximately 1.6%, (w/v) diclofenacsodium and between approximately 0.1% and approximately 0.5%, such asbetween approximately 0.3% and approximately 0.35%, (w/v) lidocainehydrochloride. In one embodiment, the compounded topical solutionincludes approximately 1.47% (w/v) diclofenac sodium and approximately0.333% (w/v) lidocaine hydrochloride. In another embodiment, thecompounded topical solution includes approximately 1.35% (w/v)diclofenac and approximately 0.4% (w/v) lidocaine. In variousembodiments, a method of formulating the compounded topical solutionincludes combining a commercially available diclofenac sodium solution,diclofenac sodium topical solution, 1.5% (w/w), or diclofenac sodiumtopical solution 2.0% (w/w) solution, with a commercially availablelidocaine solution, such as lidocaine hydrochloride topical solution, 4%USP, to form a compounded topical solution having one of the abovelisted concentrations (w/v) of diclofenac sodium and lidocainehydrochloride. Stronger or weaker concentrations of diclofenac ordiclofenac sodium topical solutions and lidocaine or lidocainehydrochloride topical solutions may be used wherein the amounts of suchsolutions added are modified to achieve the appropriate w/vconcentrations.

In various embodiments, the compounded topical solution comprises acommercially available diclofenac sodium topical solution, 1.5% (w/w),compounded with a commercially available lidocaine hydrochloride topicalsolution, 4% USP, wherein the compounded topical solution includesdiclofenac sodium topical solution, 1.5% (w/w), at a concentrationbetween 0.1% and 99%, such as between 50% and 95%, (v/v) and lidocainehydrochloride topical solution, 4% USP, at a concentration between 0.1%and 90%, such as 0.2% and 5%, (v/v). In one example, the compoundedtopical solution includes approximately 80% or more, approximately 90%or more, or approximately 91.7% (v/v) diclofenac sodium topicalsolution, 1.5% (w/w), and approximately 4% or more, approximately 7% ormore, or approximately 8.32% (v/v) lidocaine hydrochloride topicalsolution, 4% USP. In one embodiment, the compounded topical solutionincludes approximately 90% (v/v) diclofenac sodium topical solution,1.5% (w/w), and approximately 10% (v/v) lidocaine hydrochloride topicalsolution, 4% USP. In some embodiments, the compounded topical solutionincludes between approximately 50% and approximately 98%, approximately55% and approximately 97%, approximately 60% and approximately 96%,approximately 70% and approximately 95%, approximately 80% andapproximately 95%, approximately 85% and approximately 95%,approximately 90% and approximately 95%, approximately 90% andapproximately 94%, approximately 90% and approximately 93%,approximately 90% and approximately 92%, approximately 91% andapproximately 93%, approximately 91% and approximately 92% (v/v)diclofenac sodium topical solution, 1.5% (w/w), and betweenapproximately 2% and approximately 20%, approximately 4% andapproximately 18%, approximately 6% and approximately 16%, approximately6% and approximately 16%, approximately 6% and approximately 12%,approximately 6% and approximately 10%, approximately 7% andapproximately 14%, approximately 7% and approximately 12%, approximately7% and approximately 10%, approximately 8% and approximately 14%,approximately 8% and approximately 12%, approximately 8% andapproximately 10% (v/v) lidocaine hydrochloride topical solution, 4%USP. For example, in various embodiments, the compounded topicalsolution comprises between approximately 80% and approximately 95%, suchas between approximately 90% and approximately 93% (v/v) diclofenacsodium topical solution, 1.5% (w/w), and between approximately 4% andapproximately 14%, such as between approximately 7% and approximately10% (v/v) lidocaine hydrochloride topical solution, 4% USP. In oneembodiment, the compounded topical solution includes approximately 91.7%diclofenac sodium and approximately 8.32% lidocaine hydrochloridetopical solution, 4% USP. In various embodiments, a method offormulating the compounded topical solution includes combining acommercially available diclofenac sodium solution, such as diclofenacsodium topical solution, 1.5% (w/w), with a commercially availablelidocaine solution, such as lidocaine hydrochloride topical solution, 4%USP, to form a compounded topical solution having one of the abovelisted concentrations (v/v) of diclofenac sodium topical solution, 1.5%(w/w), and lidocaine hydrochloride topical solution, 4% USP. Stronger orweaker concentrations of diclofenac or diclofenac sodium topicalsolutions and lidocaine or lidocaine hydrochloride topical solutions maybe used wherein the amounts of such solutions added are modified toachieve the appropriate v/v concentrations.

As introduced above, a method of making a compounded topical solutionmay include combining, e.g., adding to each other, two commerciallyavailable topical solutions. The method may further include mixing thetwo combined solutions to form a compounding topical solution foradministration of multiple active agents. Example 1 presents a method ofmaking a compounded topical solution that includes approximately 1.47%diclofenac sodium (w/v) and approximately 0.333% (w/v) lidocainehydrochloride. However, the method may be applied to make compoundedtopical solutions having other active concentrations, such as thosedescribed herein.

Example 1—Diclofenac Sodium/Lidocaine HCl Compounded Topical Solution1.47/0.333%

Diclofenac sodium topical solution, 1.5% (w/w), and lidocainehydrochloride topical solution, 4% USP, were compounded to make acompounded topical solution. Appropriate amounts of diclofenac sodiumtopical solution, 1.5% (w/w), and lidocaine hydrochloride topicalsolution, 4% USP, were measured. Diclofenac sodium topical solution,1.5% (w/w), includes approximately 16.05 mg diclofenac sodium per mL.Accordingly, approximately 0.9167 mL of diclofenac sodium topicalsolution, 1.5% (w/w), was measured for every mL of compounded topicalsolution. Approximately 0.0832 mL of lidocaine hydrochloride topicalsolution, 4% USP, was measured for every mL of compounded topicalsolution. The measured ingredients where combined in a beaker. Thebeaker was placed on a magnetic stirring plate and a stir bar was placedin the beaker and rotated at a speed to create a small vortex for 5minutes. The stirred solution was then placed in containers. Each mL ofthe compounded topical solution included approximately 91.7% (v/v)diclofenac sodium topical solution, 1.5% (w/w), and approximately 8.32%lidocaine hydrochloride topical solution, 4% USP.

Table I below depicts potency test results for the compounded topicalsolution of Example 1. Potency was determined via USP<621>HPLC,USP<851>Spectrophotometry, and specific monograph, using a HighPerformance Liquid Chromatography with an Ultraviolet/Photodiode ArrayDetector.

TABLE I Potency Test Test Analyte Reported Measured Potency MethodLidocaine 0.333% 0.336% 101% HPLC with an Hydrochloride Ultraviolet/photodio de array Diclofenac 1.47  1.51% 103% HPLC Sodium

In further embodiments, the method may also include combining one ormore additional active agents comprising one or more additional NSAIDsselected from salicylic acid derivatives (e.g., aspirin, diflunisal,salsalate, trilisate), one or more propionic acids (e.g., flurbiprofen,ibuprofen, ketoprofen, naproxen, oxaprozin), one or more acetic acids(e.g., etodolac, indomethacin, ketorolac, nabumetone, sulindac,tolmetin), one or more fenamates (e.g., meclofenamate), one or moreoxicams (meloxicam, piroxicam), or one or more COX-2 inhibitors (e.g.,celecoxib, rofecoxib, valdecoxib), or combinations thereof, one or moreadditional local anesthetics selected from prilocaine, benzocaine, orcombination thereof, one or more muscle relaxants selected frombaclofen, carisoprodol, orphenadrine, cyclobenzaprine, dantrolene,tizanidine, amitriptyline, or combinations thereof, one or more NMDAreceptor antagonists such as ketamine, or one or more opioid or opiateagonists selected from oxycodone, morphine, fentanyl, hydrocodone,codeine, butalbital, tramadol, or combinations thereof, one or morenerve depressants selected from gabapentin, topiramate, lamotrigine, orcombinations thereof, and/or other active agents. The additional activeagents may be provided in powder form (e.g., pure powder or crushedtablets), suspension, gel, solution, or cream, e.g., emulsion. Theadditional active agents may comprise 0.1% to 5% (w/v) of the compoundedtopical solution.

In further embodiments, the compounded topical solution may be furthercompounded with a cream to form a compounded transdermal cream fortopical/transdermal administration. As used herein, cream is intended toinclude a cream, ointment, lotion, gel, emulsion (oil in water or waterin oil), etc. unless stated otherwise. In some embodiments, thecompounded topical solution is compounded with a commercially availablecream, which may or may not include additional active agents.

The compounded topical solution or derivative thereof may be topicallyapplied to a body surface utilizing for example, spray, drops, atomizer,wash, swab, sponge, absorbent dressing, instillation or irrigation.Topical application may be with respect to body surfaces such as trunk,limbs, hands, feet, neck, head, cavities, etc. In various embodiments,the compounded topical solution may find orthopedic application, e.g.,as part of a therapeutic treatment of rheumatoidarthritis/osteoarthritis, lateral epicondylitis (tennis elbow), medialepicondylitis (golfer's elbow), chondromalacia patellae—CMP (runner'sknee), or tendonitis/carpel tunnel; rheumatologic application, e.g., aspart of a therapeutic treatment of soft tissue pain, fibromyalgia,diabetic neuropathy, peripheral neuropathy, rheumatoid arthritis, orosteoarthritis; neurologic application, e.g., as part of a therapeutictreatment diabetic neuropathy, peripheral neuropathy, fibromyalgia, orlocalized pain; podiatric application, e.g., as part of a therapeutictreatment of diabetic neuropathy, peripheral neuropathy, plantarfasciitis, Achilles tendonitis, tarsal tunnel—post-op massage, or heelpain—which may include usage in conjunction with urea; pain managementapplication, e.g., as part of a therapeutic treatment of soft tissuepain, fibromyalgia, diabetic/peripheral neuropathy, rheumatoidarthritis, osteoarthritis, or neck and back pain; or ear nose and throator dental applications, e.g., as part of a therapeutic treatment oftemporomandibular joint disorder (TMJD or TMJ), or trigeminal neuralgia.

The present disclosure also includes a stability-indicating method forthe analysis of compounded solutions. As presented in the followingexample forced degradation study performed on a compounded solutionpreparation comprising Diclofenac Sodium/Lidocaine HCl Solution1.47%/0.333%, the methods used are stability-indicating. The methodsdescribed below and similar may be used to establishstability-indicating methods for analysis of other compounded solutionsusing similarly designed forced degradation studies.

At least two degradation conditions may be used to determinespecificity. In the exemplary protocol, two degradation conditions, heatand acid, were used. With respect to the heat degradation condition, 1gram samplings of the preparation were heated at 40° C., 65° C., and 80°C. At day 2, day 6, and day 8 the treated samples were taken out andanalyzed. With respect to the acid degradation condition, 120 uL of 0.1NHCl was added to 1 gram samplings of the preparation. The aciddegradation treated samplings were then either kept at room temperatureor heated at 40° C. and 65° C. At day 2, day 6, and day 8, the treatedsamplings were taken out and analyzed. Acid degradation condition alsoincluded 0.333 mL of sample incubated with 0.333 mL of concentratedsulfuric acid at 40° C. and 65° C. These treated samples where thenanalyzed after 14 hours and 18 hours of incubation. The 0.333 mL sampleswere prepared for analysis by dilution to 50 mL with methanol. Samplingsof the heat and acid treated preparations were treated the same way.Lidocaine standard was prepared by accurately weighing and dissolvingLidocaine Hydrochloride USP Monohydrate (PCCA, C169931) in Methanol to afinal concentration of 100 μg/mL. Diclofenac standard was prepared byaccurately weighing and dissolving Diclofenac Sodium USP (PCCA, C164795)in Methanol to a similar final concentration.

Standards and samples for were analyzed with a gradient method on aWaters Acquity UPLC equipped with a PDA detector. Eluent A was preparedby adding 1 mL of Trifluroacetic acid to 1 L of Dl Water. Eluent B wasprepared by adding 1 mL of Trifluoroacetic acid to 1 L of Acetonitrile.The flow rate was 1 mL per minute. The column temperature was 50° C. Theinjection volume was 2 uL. The sample tray was kept at 22° C. The LCcolumn was Acclaim RSLC PA2 Polar Advantage II, 2.2 um 120 A 2.1×150 mmfrom Thermo Scientific. The analysis time was 14 minutes with anadditional 1 minute delay. The gradient was set as described in TableII. The processing wavelengths were 225 nm for Lidocaine and 276 nm forDiclofenac Sodium.

TABLE II Gradient Used for Analysis of Standards and Samples MinutesEluent A % Fluent B % 0 98.0 2.0 6 88.0 12.0 13 20.0 80.0 13.2 98.0 2.0

Percent recoveries of Diclofenac Sodium for untreated and treatedsamples are shown in Table III. FIGS. 1A-1E present exemplarychromatograms of standard, untreated, heat treated, acid treated at 45°C., and acid treated at 65° C. Diclofenac Sodium samples, respectively.Retention time for Diclofenac Sodium is at 11.5 minutes.

TABLE III Recovery of Diclofenac Sodium (%) Day 0 Day 2 Day 6 Day 8Untreated 103 104 104 104 40° C. 106 103 105 65° C. 106 101 103 80° C.99.6 95.6 89.4 H+, RT 86.3 63.3 57.0 H+, 40° C. 70.8 44.5 28.0 H+, 65°C. 33.3 0.0 0.0 RT = 22-25° C.

Percent recoveries of Lidocaine HCl for untreated and treated samplesare shown in Table IV. FIGS. 2A-2D present exemplary chromatograms ofstandard, untreated, heat treated, and an acid treated Lidocaine HClsamples, respectively. Retention time for Lidocaine HCl is at 4.89minutes.

TABLE IV Recovery of Lidocaine HCl (%) Day 0 Day 2 Day 6 Day 8 Untreated101 101 102 104 40° C. 100 99.4 104 65° C. 108 94.5 97.5 80° C. 96.099.9 75.6 H+, RT 98.5 96.5 101 H+, 40° C. 101 103 96.4 H+, 65° C. 97.0102 101 RT = 22-25° C.

Percent recoveries of Lidocaine HCl for sulfuric acid treated samplesare shown in Table V.

TABLE V Recovery of Lidocaine HCl (%) 14 Hours 18 Hours Control 102 102H2SO4, 40° C. 96.3 75.4 H2SO4, 65° C. 86.2 73.9

The above degradation study performed for Diclofenac Sodium andLidocaine HCl Solution in Diclofenac Sodium/Lidocaine HCl Solution1.47%/0.333% shows no co-elution or interference between degradants andAPI in all samples (stressed and untreated), thus, it demonstratesspecificity. The methods used for this study are thereforestability-indicating methods.

The present disclosure may be embodied in other forms without departingfrom the spirit or essential attributes thereof and, accordingly,reference should be had to the following claims rather than theforegoing specification as indicating the scope of the invention.Further, the illustrations of arrangements described herein are intendedto provide a general understanding of the various embodiments, and theyare not intended to serve as a complete description. Many otherarrangements will be apparent to those of skill in the art uponreviewing the above description. Other arrangements may be utilized andderived therefrom, such that logical substitutions and changes may bemade without departing from the scope of this disclosure.

This disclosure is intended to cover any and all adaptations orvariations of various embodiments and arrangements of the invention.Combinations of the above arrangements, and other arrangements notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description. Therefore, it is intended thatthe disclosure not be limited to the particular preferred arrangementsdisclosed for carrying out this invention, but that the invention willinclude all embodiments and arrangements falling within the scope of theappended claims.

What is claimed is:
 1. A method of making a compounded topical solution,the method comprising: combining a diclofenac sodium topical solution,1.5% (w/w), and a lidocaine hydrochloride topical solution, 4% USP; andmixing the combined diclofenac sodium topical solution, 1.5% (w/w), andlidocaine hydrochloride topical solution, 4% USP; wherein the diclofenacsodium topical solution, 1.5% (w/w), comprises DMSO, 45.5% (w/w), andpropylene glycol and is combined in an amount between approximately 85%and approximately 95% (v/v) of the compounded topical solution and thelidocaine hydrochloride topical solution, 4% USP, is combined in anamount between approximately 5% and approximately 15% (v/v) of thecompounded topical solution.
 2. The method of claim 1, wherein thediclofenac sodium topical solution, 1.5% (w/w), is combined in an amountbetween approximately 90% and approximately 93% (v/v) of compoundedtopical solution and the lidocaine hydrochloride topical solution, 4%USP, is combined in an amount between approximately 7% and approximately10% (v/v) of the compounded topical solution.
 3. The method of claim 1,wherein the diclofenac sodium topical solution, 1.5% (w/w), is combinedin an amount approximately 90% (v/v) or more of the compounded topicalsolution and the lidocaine hydrochloride topical solution, 4% USP, iscombined in an amount approximately 7% (v/v) or more of the compoundedtopical solution.
 4. The method of claim 1, wherein the diclofenacsodium topical solution, 1.5% (w/w), is combined in an amountapproximately 91.7% (v/v) of the compounded topical solution and thelidocaine hydrochloride topical solution, 4% USP, is combined in anamount approximately 8.32% (v/v) of the compounded topical solution. 5.The method of claim 1, wherein the compounded topical solution comprisesapproximately 1.47% (w/v) diclofenac sodium and approximately 0.333%(w/v) lidocaine hydrochloride.
 6. The method of claim 1, wherein thediclofenac sodium topical solution, 1.5% (w/w), is combined in an amountbetween approximately 90% and approximately 93% (v/v) of compoundedtopical solution and the lidocaine hydrochloride topical solution, 4%USP, is combined in an amount between approximately 7% and approximately10% (v/v) of the compounded topical solution.
 7. The method of claim 6,wherein the compounded topical solution comprises approximately 1.47%(w/v) diclofenac sodium and approximately 0.333% (w/v) lidocainehydrochloride.